Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Comment
  • Published:

Understanding the molecular biology of intervertebral disc degeneration and potential gene therapy strategies for regeneration: a review

Abstract

Intervertebral disc degeneration (IVDD) is a multi-factorial process characterized by phenotypic and genotypic changes, which leads to low back pain and disability. Prolonged imbalance between anabolism and catabolism in discs alters their composition resulting in progressive loss of proteoglycans and hydration leading to IVDD. The current managements for IVDD are only able to relieve the symptoms but do not address the underlying pathology of degeneration. Researchers have tried to find out differences between the aging and degeneration of the disc. Intense attempts are in progress for identifying the various factors responsible for disc degeneration, as well as strategies for regeneration. Recently biological approaches have gained thrust in the field of IVDD. The present review illustrates the current understanding of intervertebral disc degeneration and aims to put forth recent advancements in regeneration strategies involving different biological therapies such as growth factor, cell, and gene therapy. The potentials and consequences of these therapies are also extensively discussed along with citing the most suitable method, that is, the gene therapy in detail. Initially, gene therapy was mediated by viral vectors but recent progress has enabled researchers to opt for non-virus-mediated gene therapy methods, which ensure that there are no risks of mutagenicity and infection in target cells. With constant efforts, non-virus-mediated gene therapy may prove to be an extremely powerful tool in treatment of IVDD in future.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati Met, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries. 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2163–96.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Andersson GB. Epidemiological features of chronic low-back pain. Lancet. 1999;354:581–5.

    Article  CAS  PubMed  Google Scholar 

  3. Cheung KM, Karppinen J, Chan D, Ho DW, Song YQ, Sham P, et al. Prevalence and pattern of lumbar magnetic resonance imaging changes in a population study of one thousand forty three individuals. Spine (Phila Pa 1976). 2009;34:934–40.

    Article  Google Scholar 

  4. Vadala G, Russo F, DiMartino A, Denaro VJ. Intervertebral disc regeneration: from the degenerative cascade to molecular therapy and tissue engineering. Tissue Eng Regen Med. 2015;9:679–90.

    Article  Google Scholar 

  5. Mirza SK, White AA III. Anatomy of intervertebral disc and pathophysiology of herniated disc disease. J Clin Laser Med Surg. 1995;13:131–42.

    Article  CAS  PubMed  Google Scholar 

  6. Boni M, Denaro V. Anatomo-clinical correlations in cervical spondylosis. Cervical spine. In: Kehr P, Weidner A, editors. Springer-Verlag 1. 1987; 3–20.

  7. Miller J, Schmatz C, Schultz A. Lumbar disc degeneration: correlation with age, sex, and spine level in 600 autopsy specimens. Spine. 1988;13:173–8.

    Article  CAS  PubMed  Google Scholar 

  8. Lotz JC, Ulrich JA. Innervation, inflammation, and hypermobility may characterize pathologic disc degeneration. Review of animal model data. J Bone Jt Surg Am. 2006;88:76–82.

    Google Scholar 

  9. Yoon ST. Molecular therapy of the intervertebral disc. Spine J. 2005;5:280–6S.

    Article  Google Scholar 

  10. Tow BP, Hsu WK, Wang JC. Disc regeneration: a glimpse of the future. Clin Neurosurg. 2007;54:122–8.

    PubMed  Google Scholar 

  11. Buckwalter JA. Aging and degeneration of the human intervertebral disc. Spine (Phila Pa 1976). 1995;20:1307–14.

    Article  CAS  Google Scholar 

  12. Dowdell J, Erwin M, Choma T, Vaccaro A, Iatridis J, Cho SK. Intervertebral disk degeneration and repair. Neurosurgery. 2017;80:S46–S54.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hemanta D, Jiang XX, Feng ZZ, Chen ZX, Cao YW. Etiology for degenerative disc disease. Chin Med Sci J. 2016;31:185–91. ISSN 1001-9294

    Article  PubMed  Google Scholar 

  14. Mayer JE, Iatridis JC, Chan D, Qureshi SA, Gottesman O, Hecht AC. Review: genetic polymorphisms associated with intervertebral disc degeneration. Spine J. 2013;13:299–317.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Seki S, Kawaguchi Y, Chiba K, Mikami Y, Kizawa H, Oya T, et al. A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease. Nat Genet. 2005;37:607–12.

    Article  CAS  PubMed  Google Scholar 

  16. Videman T, Saarela J, Kaprio J, Nakki A, Levalahti E, Gill K, et al. Associations of 25 structural, degradative, and inflammatory candidate genes with lumbar disc desiccation, bulging, and height narrowing. Arthritis Rheum. 2009;4:470–81.

    Article  CAS  Google Scholar 

  17. Blanquer SBG, Grijpma DW, Poot AA. Delivery systems for the treatment of degenerated intervertebral discs. Adv Drug Deliv Rev. 2015;84:172–87.

    Article  CAS  PubMed  Google Scholar 

  18. Molinos M, Almeida CR, Caldeira J, Cunha C, Goncalves RM, Barbosa MA. Inflammation in intervertebral disc degeneration and regeneration. JR Soc Interface. 2015;12:20141191.

    Article  CAS  Google Scholar 

  19. Risbud MV, Shapiro IM. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol. 2014;10:44–56.

    Article  CAS  PubMed  Google Scholar 

  20. Rizvi MR. Novel treatment strategies for intervertebral disc degeneration. Saudi J Health Sci. 2015;4:5–15.

    Article  Google Scholar 

  21. Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res. 1965;37:614–36.

    Article  CAS  PubMed  Google Scholar 

  22. Kepler CK, Ponnappan RK, Tannoury CA, Risbud MV, Anderson DG. The molecular basis of intervertebral disc degeneration. Spine J. 2013;13:318–30.

    Article  PubMed  Google Scholar 

  23. Feng C, Liu H, Yang M, Zhang Y, Huang B, Zhou Y, et al. Disc cell senescence in intervertebral disc degeneration: causes and molecular pathways. Cell Cycle. 2016;15:1674–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ding F, Shao Z, Xiong L. Cell death in intervertebral disc degeneration. Apoptosis. 2013;18:777–85.

    Article  PubMed  Google Scholar 

  25. Kadow T, Sowa G, Vo N, Kang JD. Molecular basis of intervertebral disc degeneration and herniations: what are the important translational questions? Clin Orthop Relat Res. 2015;473:1903–12.

    Article  PubMed  Google Scholar 

  26. Navani A, Ambach MA, Wei JJ, Gupta D. Biologic therapies for intervertebral degenerative disc disease: a review of novel applications. J Stem Cells Res Rev Rep. 2017;4:10–23.

    Google Scholar 

  27. Radcliff KE, Kepler CK, Jakoi A, Sidhu JS, Rihn J, Vaccaro AR, et al. Adjacent segment disease in the lumbar spine following different treatment interventions. Spine J. 2013;13:1339–49.

    Article  PubMed  Google Scholar 

  28. Vadala G, Russo F, Ambrosio L, Loppini M, Denaro V. Stem cells sources for intervertebral disc regeneration. World J Stem Cells. 2016;8:185–201.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Masuda K, An HS. Growth factors and the intervertebral disc. Spine J. 2004;4:330S–340S.

    Article  PubMed  Google Scholar 

  30. Thompson JP, Oegema TR Jr, Bradford DS. Stimulation of mature canine intervertebral disc by growth factors. Spine (Phila Pa 1976). 1991;16:253–60.

    Article  CAS  Google Scholar 

  31. Osada R, Ohshima H, Ishihara H, Yudoh K, Sakai K, Matsui H, et al. Autocrine/paracrine mechanism of insulin- like growth factor-1 secretion, and the effect of insulin-like growth factor-1 on proteoglycan synthesis in bovine intervertebral discs. J Orthop Res. 1996;14:690–9.

    Article  CAS  PubMed  Google Scholar 

  32. Takegami K, An HS, Kumano F, Chiba K, Thonar EJ, Singh K, et al. Osteogenic protein-1 is most effective in stimulating nucleus pulposus and annulus fibrosus cells to repair their matrix after chondroitinase ABC-induced in vitro chemonucleolysis. Spine J. 2005;5:231–8.

    Article  PubMed  Google Scholar 

  33. Li X, Leo BM, Beck G, Balian G, Anderson GD, et al. Collagen and proteoglycan abnormalities in the GDF-5-deficient mice and molecular changes when treating disk cells with recombinant growth factor. Spine (Phila Pa 1976). 2004;29:2229–34.

    Article  Google Scholar 

  34. Hayes AJ, Ralphs JR. The response of foetal annulus fibrosus cells to growth factors: modulation of matrix synthesis by TGF-β1 and IGF-1. Histochem Cell Biol. 2011;136:163–75.

    Article  CAS  PubMed  Google Scholar 

  35. Lee KI, Moon SH, Kim H, Kwon UH, Kim HJ, Park SN, et al. Tissue engineering of the intervertebral disc with cultured nucleus pulposus cells using atelocollagen scaffold and growth factors. Spine. 2012;37:452–8.

    Article  PubMed  Google Scholar 

  36. Gruber HE, Norton HJ, Hanley EN Jr. Anti-apoptotic effects of IGF-1 and PDGF on human intervertebral disc cells in vitro. Spine. 2000;25:2153–7.

    Article  CAS  PubMed  Google Scholar 

  37. Pratsinis H, Kletsas D. PDGF, bFGF and IGF-I stimulate the proliferation of intervertebral disc cells in vitro via the activation of the ERK and Akt signaling pathways. Eur Spine J. 2007;16:1858–66.

    Article  PubMed  PubMed Central  Google Scholar 

  38. An HS, Masuda K, Inoue N. Intervertebral disc degeneration: biological and biomechanical factors. J Orthop Sci. 2006;11:541–52.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Kim DJ, Moon SH, Kim H, Kwon UH, Park MS, Han KJ, et al. Bone morphogenetic protein - 2 facilitates expression of chondrogenic, not osteogenic, phenotype of human intervertebral disc cells. Spine. 2003;28:2679–84.

    Article  PubMed  Google Scholar 

  40. Gilbertson L, Ahn SH, Teng PN, Studer RK, Niyibizi C, Kang JD, et al. The effects of recombinant human bone morphogenetic protein-2, recombinant human bone morphogenetic protein-12, and adenoviral bone morphogenetic protein-12 on matrix synthesis in human annulus fibrosis and nucleus pulposus cells. Spine J. 2008;8:449–56.

    Article  PubMed  Google Scholar 

  41. Masuda K, Takegami K, An H, Kumano K, Chiba K, Andersson GBJ, et al. Recombinant osteogenic protein-1 upregulates extracellular matrix metabolism by rabbit annulus fibrosus and nucleus pulposus cells cultured in alginate beads. J Orthop Res. 2003;21:922–30.

    Article  CAS  PubMed  Google Scholar 

  42. Imai Y, Okuma M, An HS, Nakagawa K, Yamada M, Muehleman C, et al. Restoration of disc height loss by recombinant human osteogenic protein-1 injection into intervertebral discs undergoing degeneration induced by an intradiscal injection of chondroitinase ABC. Spine (Phila Pa 1976). 2007;32:1197–205.

    Article  Google Scholar 

  43. Fujita N, Imai J, Suzuki T, YamadaM, Ninomiya K, Miyamoto K, et al. Vascular endothelial growth factor-A is a survival factor for nucleus pulposus cells in the intervertebral disc. Biochem Biophys Res Commun. 2008;372:367–72.

    Article  CAS  PubMed  Google Scholar 

  44. Chujo T, An HS, Akeda K, Miyamoto K, Muehleman C, Attawia M, et al. Effects of growth differentiation factor-5 on the intervertebral disc—in vitro bovine study and in vivo rabbit disc degeneration model study. Spine (Phila Pa 1976). 2006;31:2909–17.

    Article  Google Scholar 

  45. Liu Y, Kong J, Chen BH, Hu YG. Combined expression of CTGF and tissue inhibitor of metalloprotease-1 promotes synthesis of proteoglycan and collagen type II in rhesus monkey lumbar intervertebral disc cells in vitro. Chin Med J (Engl). 2010;123:2082–7.

    CAS  Google Scholar 

  46. Chen WH, Lo WC, Lee JJ, Su CH, Lin CT, Liu HY, et al. Tissue-engineered intervertebral disc and chondrogenesis using human nucleus pulposus regulated through TGF-beta1 in platelet-rich plasma. J Cell Physiol. 2006;209:744–54.

    Article  CAS  PubMed  Google Scholar 

  47. Miyamoto K, Masuda K, Kim JG, Inoue N, Akeda K, Andersson GBJ, et al. Intradiscal injections of osteogenic protein-1 restore the viscoelastic properties of degenerated intervertebral discs. Spine J. 2006;6:692–703.

    Article  PubMed  Google Scholar 

  48. Chubinskaya S, Kawakami M, Rappoport L, Matsumoto T, Migita N, Rueger DC, et al. Anti-catabolic effect of OP-1 in chronically compressed intervertebral discs. J Orthop Res. 2007;25:517–30.

    Article  CAS  PubMed  Google Scholar 

  49. Huang KY, Yan JJ, Hsieh CC, Chang MS, Lin RM. The in vivo biological effects of intradiscal recombinant human bone morphogenetic protein-2 on the injured intervertebral disc: an animal experiment. Spine (Phila Pa 1976). 2007;32:1174–80.

    Article  Google Scholar 

  50. Nagae M, Ikeda T, Mikami Y, Hase H, Ozawa H, Matsuda K, et al. Intervertebral disc regeneration using platelet-rich plasma and biodegradable gelatin hydrogel microspheres. Tissue Eng. 2007;13:147–58.

    Article  CAS  PubMed  Google Scholar 

  51. Monfett M, Harrison J, Boachie Adjei K, Lutz G. Intradiscal platelet-rich plasma (PRP) injections for discogenic low back pain: an update. Int Orthop. 2016;40:1321–8.

    Article  PubMed  Google Scholar 

  52. Vasiliadis ES, Pneumaticos SG, Evangelopoulos DS, Papavassiliou AG. Biologic treatment of mild and moderate intervertebral disc degeneration. Mol Med. 2014;20:400–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Mwale F, Roughley P, Antoniou J. Distinction between the extracellular matrix of the nucleus pulposus and hyaline cartilage: a requisite for tissue engineering of intervertebral disc. Eur Cell Mater. 2004;8:58–6.

    Article  CAS  PubMed  Google Scholar 

  54. Friedmann T, Roblin R. Gene therapy for human genetic disease? Science. 1972;175:949–55.

    Article  CAS  PubMed  Google Scholar 

  55. Sobajima S, Kim JS, Gilbertson LG, Kang JD. Gene therapy for degenerative disc disease. Gene Ther. 2004;11:390–401.

    Article  CAS  PubMed  Google Scholar 

  56. Wehling P, Schulitz KP, Robbins PD, Evans CH, Reinecke JA. Transfer of genes to chondrocytic cells of the lumbar spine- proposal for a treatment strategy of spinal disorders by local gene therapy. Spine (Phila Pa 1976). 1997;2:1092–7.

    Article  Google Scholar 

  57. Liu Y, Yu T, Ma XX, Xiang HF, Hu YG, Chen BH, et al. Lentivirus-mediated tgf-β3, ctgf and timp1 gene transduction as a gene therapy for intervertebral disc degeneration in an in vivo rabbit model. Exp Ther Med. 2016;11:1399–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Nishida K, Kang JD, Gilbertson LG, Moon SH, Suh JK, Wogt MT, et al. Modulation of the biologic activity of the rabbit intervertebral disc by gene therapy: an in vivo study of adenovirus mediated transfer of the human transforming growth factor beta 1 encoding gene. Spine. 1999;24:2419–25.

    Article  CAS  PubMed  Google Scholar 

  59. Kroeber M, Unglaub F, Wang H, Schmid C, Thomsen M, Nerlich A, et al. New in vivo animal model to create intervertebral disc degeneration and to investigate the effects of therapeutic strategies to stimulate disc regeneration. Spine (Phila Pa 1976). 2002;27:2684–90.

    Article  Google Scholar 

  60. Paul R, Haydon RC, Cheng HW, Ishikawa A, Nenadovich N, Jiang W, et al. Potential use of Sox9 gene therapy for intervertebral degenerative disc disease. Spine (Phila Pa 1976). 2003;28:755–63.

    Google Scholar 

  61. Wang H, Kroeber M, Hanke M, Ries R, Schmid C, Poller W, et al. Release of active and depot GDF-5 after adenovirus-mediated over expression stimulates rabbit and human intervertebral disc cells. J Mol Med. 2004;82:126–34.

    Article  CAS  PubMed  Google Scholar 

  62. Cui M, Wan Y, Anderson DG, Shen FH, Leo BM, Laurencin CT, et al. Mouse growth and differentiation factor-5 protein and DNA therapy potentiates intervertebral disc cell aggregation and chondrogenic gene expression. Spine J. 2008;8:287–95.

    Article  PubMed  Google Scholar 

  63. Yoon ST, Park JS, Kim KS, Li J, Attallah-Wasif ES, Hutton WC, et al. ISSLS prize winner: LMP-1 upregulates intervertebral disc cell production of proteoglycans and BMPs in vitro and in vivo. Spine. 2004;29:2603–11.

    Article  PubMed  Google Scholar 

  64. Moon SH, Nishida K, Gilbertson LG, Lee HM, Kim H, Hall RA, et al. Biologic response of human intervertebral disc cells to gene therapy cocktail. Spine (Phila Pa 1976). 2008;33:1850–5.

    Article  Google Scholar 

  65. Douglas JT. Adenoviral vectors for gene therapy. Mol Biotechnol. 2007;36:71–80.

    Article  CAS  PubMed  Google Scholar 

  66. Tripathy SK, Black HB, Goldwasser E, Leiden JM. Immune responses to transgene-encoded proteins limit the stability of gene expression after injection of replication-defective adenovirus vectors. Nat Med. 1996;2:545–50.

    Article  CAS  PubMed  Google Scholar 

  67. Lattermann C, Oxner WM, Xiao X, Li J, Gilbertson LG, Robbins PD, et al. The adeno associated viral vector as a strategy for intradiscal gene transfer in immune competent and pre-exposed rabbit. Spine (Phila Pa 1976). 2005;30:497–504.

    Article  Google Scholar 

  68. Sowa G, Westrick E, Pacek C, Coelho P, Patel D, Vadala G, et al. In vitro and in vivo testing of a novel regulatory system for gene therapy for intervertebral disc degeneration. Spine (Phila Pa 1976). 2011;36:E623–E628.

    Article  Google Scholar 

  69. Wang CF, Ruan DK, Zhang C, Wang DL, Xin HK, Zhang Y, et al. Effects of adeno associated virus-2-mediated human BMP-7 gene transfection on the phenotype of nucleus pulposus cells. J Orthop Res. 2011;29:838–45.

    Article  CAS  PubMed  Google Scholar 

  70. Ren S, Liu Y, Ma J, Liu Y, Diao Z, Yang D, et al. Treatment of rabbit intervertebral disc degeneration with co-transfection by adeno-associated virus-mediated SOX9 and osteogenic protein-1 double genes in vivo. Int J Mol Med. 2013;32:1063–8.

    Article  CAS  PubMed  Google Scholar 

  71. Brown MD, Schatzlein AG, Uchegbu IF. Gene delivery with synthetic (nonviral) carriers. Int J Pharm. 2001;29:1–21.

    Article  Google Scholar 

  72. Yin H, Kanasty RL, Eltoukhy AA, Vegas AJ, Dorkin JR, Anderson DG, et al. Non-viral vectors for gene-based therapy. Nat Rev Genet. 2014;8:541–55.

    Article  CAS  Google Scholar 

  73. Chung SA, Wei AQ, Connor DE, Webb GC, Molloy T, Pajic M, et al. Nucleus pulposus cellular longevity by telomerase gene therapy. Spine (Phila Pa 1976). 2007;32:1188–96.

    Article  Google Scholar 

  74. Nishida K, Doita M, Takada T, Kakutani K, Miyamoto H, Shimomura T, et al. Sustained transgene expression in intervertebral disc cells in vivo mediated by microbubble-enhanced ultrasound gene therapy. Spine (Phila Pa 1976). 2006;31:1415–9.

    Article  Google Scholar 

  75. Zhao B, Lu M, Wang D, Li H, He X. Genome-wide identification of long noncoding RNAs in human intervertebral disc degeneration by RNA sequencing. BioMed Res Int. 2016; 2016: Article ID 3684875.

  76. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC, et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391:806–11.

    Article  CAS  PubMed  Google Scholar 

  77. Bernstein E, Caudy AA, Hammond SM, Hannon GJ. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature. 2001;409:363–6.

    Article  CAS  PubMed  Google Scholar 

  78. Kakutani K, Nishida K, Uno K, Takada T, Shimomura T, Maeno K, et al. Prolonged down regulation of specific gene expression in nucleus pulposus cell mediated by RNA interference in vitro. J Orthop Res. 2006;24:1271–8.

    Article  CAS  PubMed  Google Scholar 

  79. Suzuki T, Nishida K, Kakutani K, Maeno K, Yurube T, Takada T, et al. Sustained long-term RNA interference in nucleus pulposus cells in vivo mediated by unmodified small interfering RNA. Eur Spine J. 2009;18:263–70.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Seki S, Asanuma-Abe Y, Masuda K, Kawaguchi Y, Asanuma K, Muehleman C, et al. Effect of small interference RNA (siRNA) for ADAMTS5 on intervertebral disc degeneration in the rabbit anularneedlev puncture model. Arthritis Res Ther. 2009;11:R166.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Sudo H, Minami A. Caspase 3 as a therapeutic target for regulation of intervertebral disc degeneration in rabbits. Arthritis Rheum. 2011;63:1648–57.

    Article  CAS  PubMed  Google Scholar 

  82. Yamada K, Sudo H, Iwasaki K, Sasaki N, Higashi H, Kameda Y, et al. Caspase 3 silencing inhibits biomechanical overload induced intervertebral disk degeneration. Am J Pathol. 2014;184:753–64.

    Article  CAS  PubMed  Google Scholar 

  83. Wang C, Wang WJ, Yan YG, Xiang YX, Zhang J, Tang ZH, et al. MicroRNA: new players in intervertebral disc degeneration. Clin Chim Acta. 2015;450:333–41.

    Article  CAS  PubMed  Google Scholar 

  84. Zhou X, Chen L, Grad S, Alini M, Pan H, Yang D, et al. The roles and perspectives of microRNAs as biomarkers for intervertebral disc degeneration. J Tissue Eng Regen Med. 2017;3:1–7.

    CAS  Google Scholar 

  85. Wang KC, Chang HY. Molecular mechanisms of long noncoding RNAs. Mol Cell. 2011;43:904–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lee C, Kikyo N. Strategies to identify long noncoding RNAs involved in gene regulation. Cell Biosci. 2012;2:37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ørom UA, Derrien T, Beringer M, Gumireddy K, Gardini A, Bussotti G, et al. Long noncoding RNAs with enhancer-like function in human cells. Cell. 2010;143:46–58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Wan ZY, Song F, Sun Z, Chen YF, Zhang WL, Samartzis D, et al. Aberrantly expressed long noncoding RNAs in human intervertebral disc degeneration: a microarray related study. Arthritis Res Ther. 2014;16:465.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Chen Y, Ni H, Zhao Y, Chen K, Li M, Li C, et al. Potential role of lncRNAs in contributing to pathogenesis of intervertebral disc degeneration based on microarray data. Medical Science Monitor. Int Med J Exp Clin Res. 2015;21:3449–58.

    CAS  Google Scholar 

  90. Chen WK, Yu XH, Yang W, Wang C, He WS, Yan YG, et al. lncRNAs: novel players in intervertebral disc degeneration and osteoarthritis. Cell Prolif. 2017;50:50. n/a, e12313

    Google Scholar 

  91. Gewirtz AM, Sokol DL, Ratajczak MZ. Nucleic acid therapeutics: state of the art and future prospects. Blood. 1998;92:712–36.

    CAS  PubMed  Google Scholar 

  92. Kanwar JR, Jhankaranarayanan JS, Gurudevan S, Kanwar RK. Aptamer-based therapeutics of the past, present and future: from the perspective of eye-related diseases. Drug Discov Today. 2014;19:1309–132.

    Article  CAS  PubMed  Google Scholar 

  93. Oliveira C, Ribeiro AJ, Veiga F, Silveira I. Recent advances in nucleic acid-based delivery: from bench to clinical trials in genetic diseases. J Biomed Nanotechnol. 2016;12:841–62.

    Article  CAS  PubMed  Google Scholar 

  94. Ferree B. Use of extracellular matrix tissue to preserve cultured cell phenotype.2003/02/06/ Google Patents.

  95. Xin H, Zhang C, Wang D, Shi Z, Gu T, Wang C, et al. Tissue-engineered allograft intervertebral disc transplantation for the treatment of degenerative disc disease: experimental study in a beagle model. Tissue Eng Part A. 2013;19:143–51.

    Article  CAS  PubMed  Google Scholar 

  96. Yi Z, Guanjun T, Lin C, Zifeng P. Effects of transplantation of hTIMP1-expressing bone marrow mesenchymal stem cells on the extracellular matrix of degenerative intervertebral discs in an in vivo rabbit model. Spine. 2014;39:E669–75.

    Article  PubMed  Google Scholar 

  97. Lu K, Li H, Yang K, Wu J, Cai X, Zhou Y, et al. Exosomes as potential alternatives to stem cell therapy for intervertebral disc degeneration: in-vitro study on exosomes in interaction of nucleus pulposus cells and bone marrow mesenchymal stem cells. Stem Cell Res Ther. 2017;8:108.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Ren XF, Diao ZZ, Xi YM, Qi ZH, Ren S, Liu YJ, et al. Adeno-associated virus-mediated BMP-7 and SOX9 in vitro co-transfection of human degenerative intervertebral disc cells. Genet Mol Res. 2015;14:3736–44.

    Article  CAS  PubMed  Google Scholar 

  99. Akeda K, An HS, Pichika R, Attawia M, Thonar EJ, Lenz ME, et al. Platelet-rich plasma (PRP) stimulates the extracellular matrix metabolism of porcine nucleus pulposus and annulus fibrosus cells cultured in alginate beads. Spine. 2006;31:959–67.

    Article  PubMed  Google Scholar 

  100. Chen WH, Liu HY, Lo WC, Wu SC, Chi CH, Chang HY, et al. Intervertebral disc regeneration in an ex vivo culture system using mesenchymal stem cells and platelet-rich plasma. Biomaterials. 2009;30:5523–33.

    Article  CAS  PubMed  Google Scholar 

  101. Pirvu TN, Schroeder JE, Peroglio M, Verrier S, Kaplan L, Richards RG, et al. Platelet-rich plasma induces annulus fibrosus cell proliferation and matrix production. Eur Spine J. 2014;23:745–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Cho H, Holt D, Smith R, Hasty K, Gardocki R, Kim S, et al. The effects of platelet-rich plasma on halting the progression in porcine intervertebral disc degeneration. Artif Organs. 2016;40:190–5.

    Article  CAS  PubMed  Google Scholar 

  103. Walsh AJ, Bradford DS, Lotz JC. In vivo growth factor treatment of degenerated intervertebral discs. Spine. 2004;29:156–63.

    Article  PubMed  Google Scholar 

  104. Sawamura K, Ikeda T, Nagae M, Okamoto S, Mikami Y, Hase H, et al. Characterization of in vivo effects of platelet-rich plasma and biodegradable gelatin hydrogel microspheres on degenerated intervertebral discs. Tissue Eng Part A. 2009;15:3719–27.

    Article  CAS  PubMed  Google Scholar 

  105. Obata S, Akeda K, Imanishi T, Masuda K, Bae W, Morimoto R, et al. Effect of autologous platelet rich plasma-releasate on intervertebral disc degeneration in the rabbit anular puncture model: a preclinical study. Arthritis Res Ther. 2012;14:R241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Levi D, Horn S, Tyszko S, Levin J, Hecht-Leavitt C, Walko E, et al. Intradiscal platelet-rich plasma injection for chronic discogenic low back pain: preliminary results from a prospective trial. Pain Med. 2016;17:1010–22.

    PubMed  Google Scholar 

  107. Navani A, Hames A. Platelet-rich plasma injections for lumbar discogenic pain: a preliminary assessment of structural and functional changes. Tech Reg Anesth Pain Med. 2015;19:38–44.

    Article  Google Scholar 

  108. Paglia D, Singh H, Karukonda T, Drissi H, Moss I. PDGF-BB delays degeneration of the intervertebral discs in a rabbit preclinical model. Spine. 2016;41:E449–E458.

    Article  PubMed  Google Scholar 

  109. Feng G, Zhao X, Liu H, Zhang H, Chen X, Shi R, et al. Transplantation of mesenchymal stem cells and nucleus pulposus cells in a degenerative disc model in rabbits: a comparison of 2 cell types as potential candidates for disc regeneration. J Neurosurg Spine. 2011;14:322–29.

    Article  PubMed  Google Scholar 

  110. Vadala G, Sowa G, Hubert M, Gilbertson LG, Denaro V, Kang JD, et al. Mesenchymal stem cells injection in degenerated intervertebral disc: cell leakage may induce osteophyte formation. J Tissue Eng Regen Med. 2011;6:348–55.

    Article  PubMed  CAS  Google Scholar 

  111. Acosta FL Jr, Metz L, Adkisson HD, Liu J, Carruthers-Lienbenberg E, Milliman C, et al. Porcine intervertebral disc repair using allogeneic juvenile articular chondrocytes or mesenchymal stem cells. Tissue Eng Part A. 2011;17:3045–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hegewald AA, Endres M, Abbushi A, Cabraja M, Woiciechowsky C, Schmieder K, et al. Adequacy of herniated disc tissue as a cell source for nucleus pulposus regeneration. J Neurosurg Spine. 2011;14:273–80.

    Article  PubMed  Google Scholar 

  113. Salzig D, Schmiermund A, Gebauer E, Fuchsbauer HL, Czermak P. Influence of porcine intervertebral disc matrix on stem cell differentiation. J Funct Biomater. 2011;2:155–72.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Chan SC, Gantenbein-Ritter B. Intervertebral disc degeneration or repair with biomaterials and stem cell therapy-feasible or fiction? Swiss Med Wkly. 2012;142:w13598.

    PubMed  Google Scholar 

  115. Mwale F, Wang HT, Roughley P, Antoniou J, Haglund L. Link N and mesenchymal stem cells can induce regeneration of the early degenerate intervertebral disc. Tissue Eng Part A. 2014;20:2942–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Yim RL, Lee JT, Bow CH, Meij B, Leung V, Cheung KM, et al. A systematic review of the safety and efficacy of mesenchymal stem cells for disc degeneration: insights and future directions for regenerative therapeutics. Stem Cells Dev. 2014;23:2553–67.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Pettine K, Suzuki R, Sand T, Murphy M. Treatment of discogenic back pain with autologous bone marrow concentrate injection with minimum two year follow-up. Int Orthop. 2016;40:135–40.

    Article  PubMed  Google Scholar 

  118. Wallach CJ, Sobajima S, Watanabe Y, Kim JS, Georgescu HI, Robbins P, et al. Gene transfer of the catabolic inhibitor TIMP-1 increases measured proteoglycans in cells from degenerated human intervertebral discs. Spine. 2003;28:2331–7.

    Article  PubMed  Google Scholar 

  119. Le Maitre CL, Freemont AJ, Hoyland JA. A preliminary in vitro study into the use of IL-1Ra gene therapy for the inhibition of intervertebral disc degeneration. Int J ExpPathol. 2006;87:17–28.

    Google Scholar 

  120. Zhang CC, Cui GP, Hu JG, Xiao YZ, Zhou XS, Shao C, et al. Effects of adenoviral vector expressing hIGF-1 on apoptosis in nucleus pulposus cells in vitro. Int J Mol Med. 2014;33:401–5.

    Article  PubMed  CAS  Google Scholar 

  121. Zhang YH, Zhao CQ, Jiang LS, Dai LY. Lentiviral shRNA silencing of CHOP inhibits apoptosis induced by cyclic stretch in rat annular cells and attenuates disc degeneration in the rats. Apoptosis. 2011;6:594–605.

    Article  CAS  Google Scholar 

  122. Leckie SK, Bechara BP, Hartman RA, Sowa GA, Woods BI, Coelho JP, et al. Injection of AAV2-BMP2 and AAV2-TIMP1 into the nucleus pulposus slows the course of intervertebral disc degeneration in an in vivo rabbit model. Spine J. 2012;12:7–20.

    Article  PubMed  Google Scholar 

  123. Zhao B, Yu Q, Li H, Guo X, He X. Characterization of microRNA expression profiles in patients with intervertebral disc degeneration. Int J Mol Med. 2014;33:43–50.

    Article  PubMed  CAS  Google Scholar 

  124. OhrtNissen S, Dossing KBV, Rossing MLajer C, Vikesa J, Neilsen FC, et al. Characterization of miRNA expression in human degenerative lumbar disks. Connect Tissue Res. 2013;54:197–203.

    Article  CAS  Google Scholar 

  125. Hu P, Feng B, Wang G, Ning B, Jia T. Microarray based analysis of gene regulation by microRNA in intervertebral disc degeneration. Mol Med Rep. 2015;12:4925–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009;9:798–809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Wang HQ, Yu XD, Liu ZH, Cheng X, Samartzis D, Jia LT, et al. Deregulated miR-155 promotes Fas-mediated apoptosis in human intervertebral disc degeneration by targeting FADD and caspase-3. J Pathol. 2011;225:232–42.

    Article  CAS  PubMed  Google Scholar 

  128. Liu G, Cao P, Chen H, Yuan W, Wang J, Tang X, et al. MiR-27a regulates apoptosis in nucleus pulposus cells by targeting PI3K. PLoS ONE. 2013;8:e75251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Yu X, Li Z, Shen J, Wu KKW, Liang J, Weng X, et al. MicroRNA-10b promotes nucleus pulposus cell proliferation through RhoC-Akt pathway by targeting HOXD10 in intervetebral disc degeneration. PLoS ONE. 2013;8:e83080.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Tsirimonaki E, Fedonidis C, Pneumaticos SG, Tragas AA, Michalopoulos I, Mangoura D, et al. PKCεsignalling activates ERK1/2, and regulates aggrecan, ADAMTS5, and miR377 gene expression in human nucleus pulposus cells. PLoS ONE. 2013;8:e82045.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Liu H, Huang X, Liu X, Xiao S, Zhang Y, Xiang T, et al. MiR-21 promotes human nucleus pulposus cell proliferation through PTEN/AKT signaling. Int J Mol Sci. 2014;15:4007–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Gu SX, Li X, Hamilton JL, Chee A, Kc R, Chen P, et al. MicroRNA-146a reduces IL-1 dependent inflammatory responses in the intervertebral disc. Gene. 2015;555:80–87.

    Article  CAS  PubMed  Google Scholar 

  133. Wang T, Li P, Ma X, Tian P, Han C, Zang J, et al. MicroRNA-494 inhibition protects nucleus pulposus cells from TNF-alpha-induced apoptosis by targeting JunD. Biochimie. 2015;115:1–7.

    Article  PubMed  CAS  Google Scholar 

  134. Jing W, Jiang W. MicroRNA-93 regulates collagen loss by targeting MMP3 in human nucleus pulposus cells. Cell Prolif. 2015;48:284–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Yan N, Yu S, Zhang H, Hou T. Lumbar disc degeneration is facilitated by miR-100-mediated FGFR3 suppression. Cell Physiol Biochem. 2015;36:2229–36.

    Article  CAS  PubMed  Google Scholar 

  136. Ji M, Zhang X, Shi P, Lu J, Wang S, Chang Q, et al. Down regulation of microRNA-193a-3p is involved in intervertebral disc degeneration by targeting MMP14. J Mol Med. 2016;94:457.

    Article  CAS  PubMed  Google Scholar 

  137. Richardson SM, Hoyland JA. Stem cell regeneration of degenerated intervertebral discs: current status. Curr Sci Inc. 2008;12:83.

    Article  Google Scholar 

  138. Li W, Wang P, Zhang Z, Wang W, Liu Y, Qi Q, et al. MiR-184 regulates proliferation in nucleus pulposus cells by targeting GAS1. World Neurosurg. 2017;97:710–15.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to extend our sincere thanks to SMART, Sunshine hospitals for helping with our work.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Subbaiah GPV MS Ortho(Spine).

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sampara, P., Banala, R.R., Vemuri, S.K. et al. Understanding the molecular biology of intervertebral disc degeneration and potential gene therapy strategies for regeneration: a review. Gene Ther 25, 67–82 (2018). https://doi.org/10.1038/s41434-018-0004-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41434-018-0004-0

This article is cited by

Search

Quick links